Somatostatin prodrugs

Abstract

The present invention provides prodrugs of somatostatin peptide and peptide analogs that are tissue permeable and oral bioavailable and enable activity of the somatostatin analog at the circulation or target tissue after cleavage of charge-masking lipophilic moieties. Pharmaceutical compositions comprising these prodrugs and their use in therapy and diagnosis are also provided.

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods for improving the permeability and oral bioavailability of somatostatin derivatives, to somatostatin prodrugs and to their use in therapy.BACKGROUND OF THE INVENTION[0002]Somatostatin is a peptide hormone involved in many different biological functions. The native somatostatin (SRIF, somatotropin release inhibitory factor), was found to have a cyclic structure joined by an intramolecular disulfide bond between two cysteine residues. In the human body, it is present in two forms, as somatostatin-14 and somatostatin-28 (14 and 28 amino acids, respectively) [1]. Somatostatin has a broad spectrum of biological actions, exerts suppressive effects on a large variety of cells, and appears to be an endogenous growth inhibitor [2]. The SRIF binds with high affinity to five different subtypes of specific SRIF receptors (SSTRs) on the cell surface, which belong to the G-protein-coupled receptor family (SSTR1, SSTR2, SSTR3, SS...

AI Technical Summary

Benefits of technology

[0011]The present invention provides prodrugs of somatostatin and somatostatin derivatives that enables oral administration without losing activity or specificity. The prodrugs of the present invention contain moieties that mask charged groups of the peptide's sequence and increases its hydrophobicity and permeability through biological membranes and thus increase bioavailability of the somatostatin compound. According to the methods of the present invention, hydrophobic masking moieties are connected to the peptide's terminal and / or side chain via a cleavable linkage that allows selective removal and release of the active drug in the circulatory system or target tissue. None limiting examples of the present invention include Octreotide prodrugs having enhanced intestinal permeability via the transcellular pathway.

[0012]The major drawback of peptides in general and somatostatin derivatives specifically, as therapeutic entities is that they require parenteral administration due to their poor intestinal permeability that attributed mainly to the charged groups of their sequence. The present invention provides methods for improving passive membrane permeation of somatostatin compounds by providing prodrugs comprising masked ionizable (charged) functional groups. Masking of ionizable functional groups of a peptide sequence reduces the polarity and charge of a peptide, and together with the hydrophobic moiety attached improves its membrane permeability.

[0013]The invention thus provides compounds with increased oral availability while maintaining their activity in the target cells and tissues following transformation into active somatostatin forms.

[0014]Prodrugs according to the present invention are poorly active or inactive compounds containing the parental somatostatin that undergoes in vivo biotransformation through chemical or enzymatic cleavage, enabling the delivery of the active compound in an effective manner and amount thus overcoming pharmacokinetic, pharmacodynamic and toxicology challenges without permanently altering the pharmacological properties of the parental drug.

[0111]In some embodiments the somatostatin-based prodrug is devoid of positively charged nitrogen atoms. In some embodiments the somatostatin-based prodrug is devoid of electrically charged nitrogen atoms. In some embodiments the somatostatin-based prodrug is having a net neutral charge. In some embodiments the somatostatin-based prodrug is devoid of positively charged atoms. In some embodiments the somatostatin-based prodrug is devoid of charged atoms. In some embodiment and as understood by a person skilled in the art, the reaction of step (b) may be facilitated in the presence of a base. Without wishing to be bound by any theory or mechanism of action, the peptide of step (a) may include protonated nitrogen atoms. Consequently, said protonated nitrogen atoms may show very low nucleophilicity and tendency to react with the alkyl chloroformate. As a result, an added base may deprotonate the protonated nitrogen atoms of the starting peptide and facilitate the reaction.

Problems solved by technology

The major drawback of peptides in general and somatostatin derivatives specifically, as therapeutic entities is that they require parenteral administration due to their poor intestinal permeability that attributed mainly to the charged groups of their sequence.

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